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Down Syndrome

Down Syndrome
One Smart Cookie

Todd T. Eckdahl
Down Syndrome: One Smart Cookie
Copyright © Momentum Press®, LLC, 2018.

All rights reserved. No part of this publication may be reproduced, stored

in a retrieval system, or transmitted in any form or by any means—
electronic, mechanical, photocopy, recording, or any other—except for
brief quotations, not to exceed 250 words, without the prior permission
of the publisher.

First published in 2018 by

Momentum Press®, LLC
222 East 46th Street, New York, NY 10017

ISBN-13: 978-1-94474-961-3 (paperback)

ISBN-13: 978-1-94474-962-0 (e-book)

Momentum Press Human Diseases and Conditions Collection

DOI: 10.5643/9781944749620

Cover and interior design by S4Carlisle Publishing Services

Private Ltd., Chennai, India

First edition: 2018

10 9 8 7 6 5 4 3 2 1

Printed in the United States of America

This book presents Down syndrome, which is the most common
­chromosomal disorder in humans, occurring at a rate of about 1 in 700
births. The book describes the characteristic physical features caused by
Down syndrome and the myriad of symptoms and health ­complications
it brings, including heart defects, congenital vision and hearing loss,
­abnormalities of the musculoskeletal system, digestive problems, ­epilepsy,
leukemia, an increased risk of infectious disease, intellectual d
­ isability, and
dementia from Alzheimer’s disease. Readers will learn about methods by
which Down syndrome can be diagnosed prenatally or at birth. Causes of
Down syndrome include errors in the distribution of ­chromosomes ­during
reproduction, and the effects of extra copies of the a­ pproximately 250 genes
on chromosome 21. The book describes a ­positive ­correlation between
maternal age and the risk of Down ­syndrome. It covers ­treatments for
Down syndrome congenital defects and health ­complications; ­approaches
to the education of children with Down ­syndrome; and ­physical, speech,
occupational, and behavioral therapies that benefit c­ hildren and adults
with Down syndrome. Future prospects for the diagnosis and treatment
of Down syndrome are presented, including experimental drugs, stem cell
therapies, a process by which embryos produced in a clinical ­laboratory
can be screened for Down syndrome before being used to establish a preg-
nancy, and several Down syndrome gene therapy strategies.

aneuploidy, chromosomal disease, Down syndrome, genetic disease, heart
defects, intellectual disability, mosaic Down syndrome, translocation
Down syndrome, trisomy 21
Chapter 1 Symptoms and Diagnosis...................................................1
Chapter 2 Causes and Contributing Factors.....................................17
Chapter 3 Treatment and Therapy....................................................35
Chapter 4 Future Prospects...............................................................45
I am grateful to my friend Malcolm Campbell for encouraging me to take
a leap of faith on this project, and on several others that have shaped my
career as a science educator. I value Malcolm as a teaching and research
collaborator, and I am proud of the positive impact that we have made
together on science education and the improvement of science literacy. I
am also grateful for the cheerful and professional support I received from
the publishing team at Momentum Press.
This book would not have been possible without the support of my
wife, Patty Eckdahl. She understands my passion for science and s­ cience
education and helps me to channel it in ways that benefit students and
others around me. I also appreciate the support and encouragement
that my parents, Tom and Bonnie Eckdahl, gave me in the pursuit of an
­education that would give me the privilege of sharing my love of DNA
and genetics with undergraduate students and everyone else I meet.
I am grateful to my undergraduate genetics professor at the University
of Minnesota, Duluth, Stephen Hedman, for helping me to understand
that I could pursue my love of genetics in graduate school. Thanks to John
Anderson at Purdue University, who taught me to conduct m ­ olecular
­genetics research and to value undergraduate education. I appreciate the
environment that Missouri Western State University provided me for
­following a path to becoming a science educator. I am grateful to my
mentors in the Missouri Western Biology Department, Rich Crumley,
Bill Andresen, John Rushin, and Dave Ashley, who helped me to learn
how to engage students in the classroom and the research lab. I a­ ppreciate
the many students that I have worked with in class and collaborated with
on research projects outside of class. I take pride in the contributions
that my former students have already made and will continue to make
to society.
Collette Divitto was born in 1990 with Down syndrome. She grew up in
Ridgefield, Connecticut, where she developed a passion for baking after
taking classes in high school. After testing out several cookie recipes, she
came up with an original cinnamon chocolate chip cookie that people
really enjoyed. Because all of her friends and family raved, “This cookie
is amazing,” Collette decided to call her recipe “The Amazing Cookie.”
After high school, Collette attended Clemson University, and finished a
3-year LIFE program in just 2 years. With characteristic sass and a strong
drive to work hard and succeed, she moved to Boston, where she was sure
she would find a paying job. Although she went on many job interviews
that seemed to go very well, she always got an email saying something
like, “it was great to meet you, Collette, but at this time we feel you are
not a good fit for our company.” Because she was determined not to let
rejection stop her from earning a living and doing meaningful work, Col-
lette decided to turn her passion for baking into a business and founded
Collettey’s Cookies. She started by approaching a local grocery store, ask-
ing if they would sell “The Amazing Cookie.” The store became her first
of many clients. Knowing firsthand the struggles that people with Down
syndrome endure while looking for employment, Collette decided that
her company would be not just a means of earning a living, but it would
have a greater mission—to create jobs for other people with disabilities.
In late 2016, the Boston CBS TV affiliate featured Collette and her com-
pany on their nightly news program. Soon, she was flooded with orders.
The national news picked up her story, and Collettey’s Cookies went
viral. She has been featured on CNN, Good Morning America, MSNBC,
Inside Edition, BBC, and many other print and television media outlets
around the world. She has sold over 180,000 cookies to date, and Col-
lettey’s Cookies now employs 13 people, several with disabilities. Collette
travels around the country to share her inspiring story, and constantly
encourages people to focus on their abilities rather than what they can’t
do. Her ultimate goal is to work with lawmakers in Washington, D.C. to

create policies that would increase employment opportunities for people

with disabilities. Collette is one smart cookie.
The namesake of Down syndrome is John Langdon Down, a British
physician who published a research paper in 1866 that drew correlations
between the physical features of people with different ethnic backgrounds
and the severity of their inherited intellectual disabilities. Down described
people with Down syndrome as “Mongolian idiots.” For the next c­ entury,
the pejorative terminology persisted as mongolism or Mongolian i­diocy,
and people who had it were referred to as Mongols, ­Mongoloids, or
­Mongolian idiots. In 1959, French physicians Marthe Gautier and Jerome
Lejeune reported their discovery that people with Down s­yndrome
had 47 chromosomes instead of the normal c­ omplement of 46. They
­discovered that the increase in chromosome number was due to the pres-
ence of three copies of chromosome 21 instead of two, which is called a
trisomy. The discovery led people in the early 1960s to refer to Down’s
namesake condition as trisomy 21 Down syndrome, which is still in
widespread use today. In 1965, the country of Mongolia sent a request
to the World Health Organization (WHO) to stop referring to trisomy
21 as ­mongolism, and to people who have it as Mongoloids. The WHO
responded to the request by adopting the name Down syndrome. In 2007,
the WHO followed the French Association for Research on Trisomy 21
and established March 21 (3-21) as World Down Syndrome Day. The
United Nations invited all of its member states to observe World Down
Syndrome Day in 2012, when Secretary-General Ban ­Ki-moon said:

On this day, let us reaffirm that persons with Down syndrome are
entitled to the full and effective enjoyment of all human rights
and fundamental freedoms. Let us each do our part to enable
­children and persons with Down syndrome to participate fully in
the development and life of their societies on an equal basis with
others. Let us build an inclusive society for all.

The statement captured worldwide progress on the perception and treat-

ment of people with Down syndrome, and called for equal o­ pportunities
for them to become contributing members of societies. World Down
Syndrome Day promotes awareness, advocates for equal o­ pportunity and

rights, and raises funds to support people with Down syndrome. Down
Syndrome International maintains a website dedicated to World Down
Syndrome Day to coordinate local and worldwide events, and provides a
forum for people to participate and share their experiences (see URL in
Many people stand to benefit from societal improvements p ­ romoted
by World Down Syndrome Day. Worldwide, there are between 6 and 9
million children and adults living with Down syndrome. The worldwide
occurrence of Down syndrome is about 1 in 700 births, which is about
130,000 babies per year. Most babies born with Down syndrome have
three copies of chromosome 21 instead of two, but 1 in 25 of them has
a chromosomal rearrangement in which part or all of chromosome 21 is
attached to another chromosome. In both cases, the extra genetic ­material
causes alterations in the embryological program of development that
result in the symptoms and health complications of Down ­syndrome.
Symptoms vary among people but can include congenital heart defects,
gastrointestinal problems, obesity, epilepsy, leukemia, dementia, Alzheim-
er’s disease, and an increased risk of certain infectious diseases. The lower
life ­expectancy for people with Down syndrome occurs primarily because
of congenital heart defects, which occur in about half of babies born with
Down syndrome. However, improved treatment in developed countries
has increased the life expectancy for people with Down syndrome from
less than 10 years a century ago, to 25 years in the 1970s, to over 60 years
today. The rise in life expectancy of people with Down syndrome and
the growing appreciation of their abilities to be educated and to pursue
work mean they are increasingly likely to make important contributions
to societies throughout the world.
This book presents Down syndrome as a genetic condition caused
by extra copies of most or all of the genes found on chromosome 21.
Chapter 1 describes characteristic physical features caused by Down syn-
drome and the myriad of symptoms and health complications it brings,
including heart defects, congenital vision and ­hearing loss, abnormalities
of the musculoskeletal system, digestive p ­ roblems, epilepsy, leukemia, an
increased risk of infectious disease, intellectual ­disability, and dementia
from Alzheimer’s disease. It also presents m ­ ethods by which Down syn-
drome can be diagnosed prenatally, or after birth. The underlying causes

of Down syndrome are detailed in Chapter 2 as errors in the process by

which chromosomes are distributed during the production of sex cells
for reproduction, and as effects of extra copies of the approximately 250
genes found on chromosome 21. Chapter 3 describes treatments for
Down syndrome congenital defects and health complications, approaches
to the education of children with Down ­syndrome, and ­physical, speech,
occupational, and behavioral therapies that b­ enefit c­hildren and adults
with Down syndrome. Future prospects for the diagnosis and treatment
of Down syndrome are presented in Chapter 4, including experimental
drugs, stem cell therapies, a process by which embryos produced in a clini-
cal laboratory can be screened for Down syndrome before being used to
establish a pregnancy, and several Down syndrome gene therapy strategies.

Symptoms and Diagnosis

Down syndrome is called a syndrome because it affects a wide variety

of organ systems. This chapter describes the effects of Down syndrome
on physical appearance; catalogs its symptoms, including heart defects,
congenital conditions affecting the musculoskeletal, digestive, and im-
mune systems, intellectual disability, and dementia from Alzheimer’s
disease; and describes additional health complications caused by Down
syndrome. The ­chapter also explains methods by which Down syndrome
can be diagnosed ­prenatally or after birth.

Down Syndrome Results in Characteristic

Physical Features
All of us have physical features that are strongly influenced by our DNA. We
have tendencies to resemble our siblings and parents, and members of our
extended families. The influence of family background on the ­appearance
of people with Down syndrome is overshadowed by the o­ ccurrence of char-
acteristic physical features (see Table 1.1), and the effect is strong enough
that people with Down syndrome often appear to be more closely related
to each other than to their families. The illusion of a close relationship
among people with Down syndrome comes from distinctive facial features,
­including a more rounded face, upwardly slanted eyes that have pronounced
­epicanthal folds, a flattened nasal bridge, a small nose, a small mouth with
a large tongue that tends to stick out more often, and crooked teeth that
are irregularly shaped. The eyes often have lightly or darkly colored spots
on the iris, which are called Brushfield spots. People with Down syndrome
tend to have small ears that are set lower on the head. The back of the head
is often flattened, and the neck is shorter and wider. Characteristic body
shape features caused by Down syndrome include short stature, short and

Table 1.1  Common Down syndrome physical features

Body part Description
Skull Small, shortened skull that is flattened on the back, sloping
forehead, missing or underdeveloped sinuses
Eyes Upward slanted and wide-set eyes, epicanthal folds, Brushfield spots
Ears Smaller ears with extra folds, ears set lower on the head
Nose Smaller nose, flattened nasal bridge
Mouth Smaller mouth, large tongue that tends to stick out more often,
undersized teeth, crooked teeth, irregularly shaped teeth
Hands Broad hands, only one crease across the palm, short fingers, curved
fifth finger
Feet Larger gap between the first and the second toe
Limbs Short and stocky arms and legs with hyperflexible joints
Body Short stature, shorter and wider neck, protruding stomach

stocky arms and legs with hyperflexible joints, and a stomach that sticks out
from poor abdominal muscle tone. The hands tend to be broad with short
fingers, and only one crease across the palm. The feet often have a larger gap
between the first and the second toe.

Congenital Heart Defects from Down Syndrome

Down syndrome affects the process by which the fetal heart is formed
during pregnancy. All early embryos are divided into three primary
germ layers that establish the overall spatial organization of the body and
­contain the progenitor cells for all tissues and organs. The heart forms
­during the third week after fertilization from mesoderm, the middle of
the three primary germ layers that also gives rise to skeletal muscle, smooth
muscle, bone, cartilage, and blood. Mesoderm cells grow, divide, migrate,
and communicate with other cells to form a primitive heart that pumps
blood throughout the fetal circulatory system to provide nutrients and
oxygen to the developing embryo, and remove carbon dioxide and other
wastes. The straight tube of cells that forms the primitive heart bends
into an “S” shape during the fourth week of development, after which
septa develop to separate the heart into four chambers. By week nine
post-conception, four valves take shape that control blood flow ­between
the heart c­ hambers, between the heart and the lungs, and b­ etween the
Symptoms and Diagnosis 3

heart and the rest of the developing embryo. The fully formed heart
pumps blood through the c­irculatory system, which includes arteries
to deliver oxygen and ­nutrients to cells and tissues, and veins to return
blood carrying carbon dioxide and waste back to the heart for removal by
other organs. The ­circulatory system has a second circulatory circuit that
delivers blood from the heart to the lungs for the exchange of oxygen and
carbon dioxide and returns blood to the heart for delivery to the rest of
the body.
About 50 percent of all infants born with Down syndrome have some
type of heart defect. A common heart defect among Down ­syndrome
infants is atrioventricular septal defect (AVSD), which occurs when the
septa that normally separate the chambers of the heart, or the valves that
control blood flow between the chambers, fail to develop properly. A
­complete AVSD incudes a hole in the septum between the two atria,
a hole in the septum between the two ventricles, and abnormal valves
between the atrial and ventricular chambers. An incomplete AVSD
occurs when there is a hole in the atrial septum and one abnormal valve.
AVSD reduces the ability of the heart to properly circulate oxygenated
blood to the body, and deoxygenated blood to the lungs, which places
an extra demand on the heart. The left ventricle normally generates high
blood pressure to circulate blood to the whole body, but the hole in the
septum between the two ventricles causes an abnormal increase in the
pressure of blood in the pulmonary artery that leads to the lungs. The
­resulting pulmonary hypertension causes the lungs to fill with blood and
­results in breathing difficulty, increased heart rate, swelling of extremities,
and cyanosis, which is a bluish skin color around the mouth, fingers,
and toes. The combined effects of AVSD on the heart and lungs often
­result in ­congestive heart failure, during which infants develop symp-
toms such as faster and heavier breathing, sweating, and tiredness that
­gradually worsen over a period of one or two months. Some infants with
a c­ omplete AVSD do not develop congestive heart failure because the
lungs are protected from increased blood pressure by constricted blood
vessels. Constricted blood vessels lead to pulmonary ­vascular disease
because of the reduced capacity to deliver oxygen to ­tissue throughout
the body. Some infants born with Down s­yndrome have a ventricular
septal defect (VSD) or an atrial septal defect (ASD), the severity of

which depends on the size and location of the hole in the septum. A small
hole may produce no symptoms, whereas larger holes cause breathlessness
and poor weight gain. Infants with Down s­ yndrome are ­sometimes born
with patent ­ductus arteriosus (PDA), which is caused by the ­abnormal
persistence of a fetal channel that connects the pulmonary artery and
the aorta prior to birth. The ductus arteriosus directs blood away
from the ­nonfun­ctioning fetal lungs that do not have access to air yet.
At birth, when the lungs fill with air and begin to f­unction, the ­ductus
arteriosus normally closes within one or two days. PDA occurs when
the ductus ­arteriosus remains open, and the consequence is p ­ ulmonary
hypertension, with symptoms that i­nclude breathing difficulty, tired-
ness, and i­ncreased heart rate. Some Down syndrome infants are born
with t­ etralogy of ­Fallot (TOF), which includes the four congenital heart
abnormalities of VSD, narrowing of the passageway to the pulmonary
artery, enlargement of the right v­ entricle, and an enlargement of the valve
leading to the aorta. These heart defects cause reduced blood flow to the
lungs, which results in rapid breathing and cyanosis.

What Other Congenital Conditions Result

from Down Syndrome?
Down syndrome results in congenital conditions that affect a variety
of body systems (Table 1.2). More than 60 percent of Down syndrome
­infants are born with vision problems, such as congenital cataracts that
cause the lens of the eye to become opaque and result in ­sensitivity
to bright light, poor night vision, and double vision. The severity of
­congenital cataracts varies from mild cases of dulled vision to severe cases
of complete ­blindness. Cataracts can also develop during childhood or
adulthood. Down syndrome infants are often born with amblyopia,
which is commonly called “lazy eye” because one eye does not move
­normally and makes a much smaller contribution to vision than the other
eye. Amblyopia occurs when the brain receives better visual input from
one eye than the other eye due to nearsightedness, cataracts, or perma-
nently crossed eyes. The symptoms of amblyopia include blurred vision,
double vision, and poor depth perception. Amblyopia often causes the
eyes to move independently of one another, instead of coordinately, which
Symptoms and Diagnosis 5

Table 1.2  Common Down syndrome congenital conditions

Body system Congenital conditions
Heart Septal defects (ASD, VSD, AVSD), PDA, TOF
Vision Refractive errors, cataracts, amblyopia, blepharitis, glaucoma
Hearing Hearing loss (conductive and sensorineural), glue ear, otitis media
Musculoskeletal Hypotonia, ligamentous laxity, atlantoaxial instability, hip
abnormalities, kneecap instability, flat feet
Digestive Hirschsprung disease, tracheoesophageal fistula, esophageal
atresia, duodenal atresia, imperforate anus, GERD
Immune Hypothyroidism, celiac disease, respiratory infections

compromises depth perception. Down syndrome also produces a higher

incidence of refractive errors that are present at birth or develop during
childhood, including farsightedness, nearsightedness, and astigmatism.
Children and adults with Down syndrome are more likely to need correc-
tive lenses. Down syndrome infants are often born with abnormal tear
ducts that easily become clogged, which causes excessive watering of the
eyes, or with blepharitis, which is recurrent inflammation of the eyelids.
Down syndrome also increases the prevalence of glaucoma, during which
abnormal drainage of the fluid inside the eye places pressure on the optic
nerve, producing the symptoms of moderate to severe eye pain, eye
redness, cloudy vision, and tunnel vision. Glaucoma can lead to perma-
nently blurred vision and eventual blindness.
Over 70 percent of Down syndrome infants are born with hearing
problems. Hearing problems are categorized as conductive hearing loss
when sound waves are not conducted properly from the outer ear to
the eardrum and the bones of the middle ear. Sensorineural hearing
loss results from dysfunction of the inner ear or its connection to the
­nervous system. Most cases of hearing loss in Down syndrome infants are
­conductive hearing loss, which is often caused by an abnormal buildup
of wax in the ear canal that prevents the conduction of sound. Down
syndrome can cause the development of a smaller ear canal that is more
susceptible to wax blockage. Conductive hearing loss in Down syndrome
infants can be also caused by glue ear, an abnormal accumulation of fluid
in the middle ear, or by otitis media, infection of the middle ear. Glue ear
and otitis media prevent the conduction of sound by the tiny bones of the

middle ear. Both causes of conductive hearing loss occur because Down
syndrome causes abnormal development of the Eustachian tube that
normally drains mucus from the middle ear. The cause of sen­sorineural
hearing loss is unknown for most people. The severity of sensorineural
hearing loss ranges from mild to profound, and it can cause hearing loss
of all sound frequencies, or it can selectively reduce hearing in the high,
medium, or low frequency ranges. Sometimes sensorineural hearing loss
develops later during childhood. It is important to distinguish between
prelingual hearing loss that occurs before a child learns to speak and
postlingual hearing loss because they present very different challenges
to language acquisition.
Another congenital problem that many Down syndrome infants have is
hypotonia, which is the occurrence of weak muscles throughout the body.
Infants with hypotonia seem “floppy” because of their weaker ­muscles, and
are often delayed in meeting developmental milestones such as r­ olling over,
sitting up, crawling, and walking. ­Hypotonia in the mouth and throat makes
it difficult for Down syndrome infants to take in and swallow breast milk
or formula, and weak muscles throughout the ­digestive tract impair diges-
tion and can lead to constipation and poor weight gain. I­ nfants with Down
syndrome are often born with ­ligamentous ­laxity due to loose ligaments
in joints throughout the body. Ligamentous laxity impairs the s­tability
of joints, making them more s­usceptible to ­hyperextension. Loose joints
contribute to an increased incidence of hip dislocations among ­children
and adolescents with Down syndrome. ­Another musculoskeletal condition
caused by Down syndrome is ­atlantoaxial instability, in which a loose
connection between neck vertebrae results in symptoms such as neck pain,
limited neck mobility, clumsiness, and walking difficulties. C­ hildren with
Down syndrome also have an increased risk of hip abnormalities, kneecap
dislocations, and flat feet.
Down syndrome infants have a higher than normal incidence of
birth defects affecting the digestive system. About 10 percent of infants
born with Down syndrome have Hirschsprung disease, which is caused
by missing nerve cell connections to the colon. Hirschsprung ­disease
­prevents normal colon function and causes intestinal blockage that can
lead to a­ bdominal swelling, vomiting, and severe constipation. About
5 ­percent of infants born with Down syndrome have a c­ ongenital defect
Symptoms and Diagnosis 7

that prevents the normal function of the gastrointestinal tract. The most
common ­examples are tracheoesophageal fistula, which is an ­abnormal
connection between the trachea and the esophagus, ­esophageal ­atresia,
which means that the esophagus does not properly connect to the
­stomach, and duodenal atresia, which is an improper connection from
the stomach to the small intestine. The symptoms of these three c­ onditions
­include frothing at the mouth, coughing, ­choking, ­abdominal swelling,
and vomiting. Down syndrome can also cause i­mperforate anus, which
means that the opening from the anus to the rectum is blocked or m ­ issing,
­resulting in a swollen abdomen and the failure to pass a stool. The con-
dition of g­astroesophageal reflux ­disorder (GERD) is characterized
by the abnormal reflux of acidic stomach contents. About 5 ­percent of
infants, children, and adults with Down syndrome have GERD, which
causes mild to severe heartburn and intolerance of certain foods. About
10 percent of people with Down syndrome have h ­ ypothyroidism, which
means the thyroid produces lower levels of the hormones that control
­metabolism throughout the body. The primary symptoms of hypothy-
roidism are fatigue, constipation, and abnormal weight gain. About 5
percent of children with Down syndrome have ­celiac disease, which is
associated with an immune reaction to gluten, and causes bloating, severe
gas, diarrhea, and anemia.

Down Syndrome Causes Delayed Development

On average, children with Down syndrome achieve physical, emotional,
and cognitive developmental milestones later than typically developing
children. Motor skills such as holding up the head, pushing up, rolling
over, sitting, standing, crawling, taking first steps, and walking, come later
to children with Down syndrome. They reach developmental milestones
that establish their independence later too, including feeding themselves
with their hands, drinking from a cup, using eating utensils, becoming
toilet trained, and dressing themselves. Children with Down syndrome are
slower than most children to achieve emotional developmental ­milestones
such as responding to smiles, expressing pleasure ­during play with ­others,
discerning the emotions of others, and developing relationships. The pro-
cess of learning how to think, known as cognitive learning, is also delayed

by Down syndrome. The limited ability of children with Down syndrome

to handle objects with fine motor skills, move about by crawling and
walking, and explore their environments means that they take in less
­information during a critical period of cognitive development. Language
plays an important role in cognition, and development of the ability to
think is delayed in children with Down syndrome because of their delay
in language acquisition. Delayed language acquisition is caused by slower
development of coordinated muscle control in the mouth and throat.
Children with Down syndrome make a slower transition from babbling
to effective spoken communication. They usually say their first word at a
time expected for most children, but thereafter, their vocabulary builds
more slowly, and they are slower to learn how to form sentences. Once
they begin speaking, they are harder to understand, a problem that is
often worsened by hearing difficulties, but enunciation usually ­improves
with age. The inability to pronounce words and organize them into
meaningful sentences usually is not a­ ccompanied by a delay in language
comprehension. Despite problems with expressing themselves orally,
children with Down syndrome develop spoken language comprehension
at a rate similar to typically developing children. U ­ nderstanding spoken
­language but not being able to speak can lead to feelings of f­ rustration for
children with Down syndrome. The d ­ evelopment of s­ hort-term memory
is also delayed in children with Down syndrome, and once it develops, it
is usually not as extensive as it is in most children. C
­ hildren with Down
syndrome usually have better short-term recall of visual i­nformation than
of verbal information. Learning how to read is easier for children with
Down syndrome than acquiring basic math skills.
Down syndrome also affects the development and maturation of
the reproductive system in both males and females. Girls with Down
syndrome begin menstruating between the ages of 10 and 14, just as
­typically developing girls do, and they usually have regular cycles, unless
they have hypothyroidism. Most sexually mature Down syndrome
women are fertile, but fertility can be lower due to a smaller number
of egg-producing follicles in the ovaries. Although men with Down
syndrome are usually infertile, there have been rare cases in which men
with Down syndrome have fathered children with the normal comple-
ment of 46 chromosomes.
Symptoms and Diagnosis 9

Cognitive Effects of Down Syndrome

Intellectual disability occurs when a child fails to fully develop the
­intellectual capacity to think, reason, learn, and understand. Children
with an intellectual disability also have trouble learning adaptive beh­avior,
which encompasses the social and practical skills needed for everyday
­living. The most common known cause of intellectual disability is Down
syndrome, and it accounts for at least 15 percent of cases ­worldwide. The
impairment of intellectual capacity varies among individuals with Down
syndrome. It ranges from severe intellectual impairment that makes
­people fully ­dependent on caregivers, to mild effects that enable people
to think and learn at levels that enable them to pursue higher ­education,
retain a job, and live independently. The most common measure of intel-
lectual capacity is the intelligence quotient (IQ), which expresses the
results of standardized intelligence tests as a ratio of mental age to chrono-
logical age. The median IQ is 100, and 96 percent of all IQ scores fall in
the range of 70–130. About 2 percent of people have an IQ below 70,
and are considered to have an intellectual disability. Most people with
Down syndrome are in this category. Those with an IQ of less than 50 are
considered to have moderate intellectual disability, whereas those with an
IQ of less than 30 have severe intellectual disability. People with Down
syndrome do not struggle as much with adaptive behavior and the devel-
opment of social skills as other people with intellectual disability.
The intellectual developmental effects of Down syndrome lead to a
­variety of mental health problems that arise in childhood, a­ dolescence,
and adulthood. Children with Down syndrome are ­susceptible to a­ nxiety,
obsessive–compulsive disorder, hyperactivity, and autism s­pectrum
­disorder. They are also more likely to be i­nattentive, ­self-absorbed,
­inflexible, and to display disruptive behaviors. ­Although children with
Down syndrome often have a cheerful demeanor, a­dolescents and
adults with Down syndrome can experience depression, extreme mood
swings, or anxiety. They often develop chronic sleep problems, and have
a four-fold increased risk of epileptic seizures. By the age of 40, about
30 percent of people with Down syndrome develop ­dementia from
­Alzheimer’s ­disease. Initial symptoms include inatte­ntion, aggres­s­ion,
irritability, lack of interest, excitability, and anxiety. Later symptoms

include memory loss, seizures, sleeplessness, and movement disorders.

The onset of dementia leads to a decline in the ability to think, reason,
and understand.

How Is Down Syndrome Diagnosed?

Prenatal tests for Down syndrome fall into the two categories of p ­ renatal
screening, which provides information about the increased risk that a
­pregnancy will result in the birth of a child with Down syndrome, and
­prenatal diagnostic testing, which diagnoses Down syndrome with
­certainty. ­Parents seek information from Down syndrome prenatal scree­
ning and diagnostic tests for several reasons. One reason is to have time to
prepare for the birth of a child with Down syndrome by informing family
members, learning about Down syndrome, and joining a support group
such as one of the 375 local affiliates of the National Down Syndrome
­Society (see URL in Bibliography). Medical professionals can also p ­ repare
for the o­ ccurrence of congenital problems that accompany Down syn-
drome, and which might require medical or surgical intervention at the time
of birth. P ­ renatal d
­ iagnosis of Down syndrome can also be used to make
the ­decision to t­erminate a pregnancy, or to offer a child with Down
­syndrome for ­adoption. Parents who already have a child with Down synd­
rome might choose to seek a prenatal diagnosis of Down s­ yndrome ­because
the risk of Down syndrome increases from 1 in 700 for the first child to 1
in 100 for the second child. The American ­Congress of ­Obstetricians and
­Gynecologists recommends that all pregnant women be o­ ffered a Down
syndrome screening test for the potential value of knowing the proba­bility
of delivering a child with Down syndrome.
One example of prenatal screening is a blood test conducted at
11 to 14 weeks of pregnancy that has a Down syndrome detection rate
of about 85 percent, and a false positive rate of 5 percent. The com-
bined test measures the levels of pregnancy-associated plasma protein A
(PAPP-A), an enzyme that controls the levels of growth hormones, and
human chorionic growth hormone (HCG), which plays important roles
in maintaining a pregnancy. Abnormal serum levels of these two ­proteins
are ­correlated with Down syndrome, and also with Edwards s­yndrome,
which is caused by an extra copy of chromosome 18. The quad screen
Symptoms and Diagnosis 11

blood test can be performed between 15 and 22 weeks of pregnancy, and

it detects about 80 percent of Down syndrome cases, with a false ­positive
rate of 5 percent. The test measures four blood constituents: HCG;
pregnancy hormones estriol and inhibin A; and serum transport p ­ rotein
­alpha-fetoprotein (AFP). The results of a quad screen provide infor­
mation about the risk of Down syndrome, Edwards syndrome, ­neural
tube ­defects, and spina bifida. Prenatal screening for Down syndrome
can also be performed with ultrasound at 11 to 14 weeks of pregnancy.
­Diagnostic ultrasound indic­ators of Down syndrome are extra thickness
of the ­nuchal fold in the neck of the developing fetus, and the absence
of the nasal bone. When ultrasound observations are combined with
the ­results of quad screen and PAPP-A blood tests, a Down syndrome
­detection rate of 95 percent can be achieved, with a false positive rate of 5
percent. Maternal blood ­screening is based on the observation that some
fetal cells cross the p ­ lacenta and can be detected in the maternal blood-
stream. Sensitive ­genetic tests can be used to detect fetal cells from among
maternal cells, and measure fetal chromosomes and genes associated with
Down syndrome or other genetic conditions. Maternal blood screening is
noninvasive to the fetus because it only involves drawing a blood sample
from the pregnant woman, and it can be performed as early as 7 weeks
of pregnancy. The detection rate of maternal blood screening for Down
syndrome is above 95 percent, with a false positive rate of 0.3 percent.
However, the probability that a fetus has Down syndrome given positive
test results is still surprising low, as calculated using Bayes’ theorem (see
URL in Bibliography). Therefore, a positive test result should prompt the
use of karyotyping as described in the next paragraph.
Due to an increase in the frequency of errors in the distribution of
chromosome 21 during the production of egg cells, the occurrence of
Down syndrome increases with maternal age. Maternal age is used in
combination with the results of prenatal screening for Down syndrome to
justify prenatal diagnostic genetic testing, which can be used to d ­ etermine
the occurrence of Down syndrome with a very high degree of certainty.
Prenatal testing for Down syndrome involves collecting fetal cells by
­amniocentesis or chorionic villus sampling (CVS) that are subjected
to genetic testing. Amniocentesis and CVS are w ­ ell-established methods
for obtaining fetal cells, but they carry a small risk to the fetus. The risk

of pregnancy complications from amniocentesis is about 0.5 p ­ ercent,

and the risk of miscarriage caused by CVS is between 0.5 and 1 percent.
­Amniocentesis is conducted between weeks 14 and 22 of ­pregnancy. A
needle is inserted through the abdominal wall and into the amniotic sac
that surrounds the fetus. Amniotic fluid containing fetal cells is withdrawn.
CVS is conducted between weeks 9 and 14 of the pregnancy. It i­nvolves
the extraction through the cervix or the a­ bdominal wall of chorion cells
from the fetal portion of the placenta. For Down syndrome diagnosis,
fetal cells collected by amniocentesis or CVS are s­ ubjected to karyotype
analysis, during which a microscopic image of the chromosomes from a
single cell is produced. The normal ­complement of human chromosomes
is 46. There are 24 different chromosomes and 2 of them, the X and the
Y chromosomes, are referred to as the sex ­chromosomes ­because they
determine sex. The other chromosomes are called a­ utosomes, and are
numbered 1 through 22 in approximate order of size (Figure 1.1). A typi-
cal karyotype reveals 22 autosomes and a pair of sex chromosomes, which
are X and Y for males, and 2 X chromosomes for females. The occurrence
of an extra copy of chromosome 21 is diagnostic of trisomy 21 Down
syndrome, which accounts for 95 percent of Down syndrome cases.
Translocation Down syndrome is diagnosed by detecting one copy of
chromosome 14 that is abnormally longer because of the addition of an
extra copy of most or all of chromosome 21. Infrequently, chromosome
3, 15, or 22 can carry the extra DNA. Translocation Down syndrome
occurs in about 4 percent of Down syndrome cases. Karyotype analysis
can also detect mosaic Down syndrome, during which some cells in the
body have an extra copy of chromosome 21, whereas other cells have the
normal complement of only two copies of chromosome 21.
Due to the inherent risks associated with amniocentesis and CVS,
many expectant parents choose to forgo prenatal diagnostic testing for
Down syndrome, even if prenatal screening warrants more definitive
­testing. Consequently, most cases of Down syndrome are diagnosed at the
time of birth. The characteristic Down syndrome physical traits ­involving
the shape of the skull, facial features, the structure of the hands and
feet, and hypotonia provide clear indications that a newborn has Down
­syndrome. However, because not all infants with Down syndrome display
the most distinguishing traits, and because these same traits can be found

Trisomy 21 Down syndrome

• Extra copy of chromosome 21
in all cells
• 95 percent of cases

1 2 3 4 5 6 7 Translocation Down syndrome

• Long arm of chromosome 21
attached to another
• 4 percent of cases 14
8 9 10 11 12 13 14 15
Mosaic Down syndrome
• Extra copy of chromosome 21 +
in some cells but not others
• 1–2 percent of cases 21 21
16 17 18 19 20 21 22 XY

Figure 1.1  Human karyotype with chromosome pairs identified and information about the three types of
Down syndrome
Symptoms and Diagnosis

among infants who do not have Down syndrome, karyotype analysis is

needed to confirm a diagnosis of Down syndrome.

Health Complications of Down Syndrome

Down syndrome produces serious health complications in children
and adults. For example, an increased risk of infections occurs because
Down syndrome compromises the immune system and causes c­ ongenital
abnormalities that provide opportunities for pathogens to flourish.
Upper respiratory infections such as sinusitis and tonsillitis, and lower
respiratory infections such as pneumonia and bronchiolitis, occur
more often in children and adults with Down syndrome because their
­airways tend to be smaller and their poor muscle tone makes coughing
less ­effective. The most common microbes in respiratory infections are the
bacterial pathogens Streptococcus pneumoniae and Haemophilus ­influenzae,
and the viral pathogen respiratory syncytial virus (RSV). Respiratory
­infection symptoms of coughing, wheezing, fever, chills, and breathing
difficulty are usually more severe for people with Down syndrome, and
it takes longer for their infections to be cleared by their compromised
­immune systems.
Children and adults with Down syndrome are more likely to get
other types of infections, too. The risk of middle ear infections (otitis
media) is increased by abnormalities in the bones and muscles of the
skull that prevent proper drainage of the fluid from the middle ear, and
by chronic upper respiratory infections. The symptoms of otitis media
­include ear pain, headache, fever, external drainage of fluid from the ear,
loss of ­balance, and hearing loss. Infants and young children with middle
ear i­nfections can display signs such as irritability, sleeplessness, loss of
­appetite, and ear tugging. Children and adults with Down syndrome
also have an increased risk of urinary tract infections, which is correlated
with a higher prevalence of congenital abnormalities in the kidneys, the
bladder, the duct that carries urine from the kidneys to the bladder, and
the duct that empties the bladder. Urinary tract infections often cause
an increased frequency of urination, and produce symptoms such as pain
in the pelvis or lower back, nausea, fever, and vomiting. Bacterial skin
infections are more common among people with Down syndrome. They
Symptoms and Diagnosis 15

sometimes develop folliculitis, which is an infection of hair follicles by

bacteria or fungi, or scabies, which is an infection by microscopic mites
that burrow under the skin.
Down syndrome also increases the risk of blood disorders such
as ­anemia, in which low blood iron content causes symptoms such as
­dizziness, breathlessness, fatigue, and increased heart rate; ­polycythemia,
in which an abnormally high red blood cell count causes headaches,
dizziness, fatigue, bruising, excessive sweating, and blurred vision;
­thrombocytopenia, which is an abnormally low platelet count that can
lead to uncontrolled bleeding; and transient myeloproliferative ­disorder
(TMD), which is caused by an production of abnormally large white
blood cells and results in fever, sweating, bruising, fatigue, h­ eadache, and
weight loss. Infants who are diagnosed with TMD should be m ­ onitored
closely because the disorder can lead to leukemia, a type of cancer in
which ­excess immature white blood cells suppress the ­formation of n ­ ormal
white blood cells. Children with Down syndrome are about 15 times
more likely to develop leukemia. The occurrence of solid tumor c­ ancers,
such as carcinoma and neuroblastoma, is lower among people with
Down syndrome. Investigations of the molecular genetic ­mechanisms by
which trisomy 21 affords protection against some cancers might yield
promising new approaches to cancer treatment.
Another health complication of Down syndrome is obstructive sleep
apnea, a sleep disorder caused by soft tissue at the back of the throat
blocking the airway, which repeatedly interrupts breathing while ­sleeping
and limits the flow of oxygen to the brain and the rest of the body. The
risk factors for obstructive sleep apnea include large neck size, a large
tongue, large tonsils, large adenoids, and sinus problems, all of which
are a­ssociated with Down syndrome. During sleep, the s­ymptoms of
­obstructive sleep apnea include cessation of breathing, sweating, ­snoring,
and ­sudden g­ asping or choking. Sleep apnea also causes ­daytime s­ leepiness,
headaches, high blood pressure, and mood changes. The disruption of
breathing ­during sleep can also have long-term effects on ­cognition and
Infants and children with Down syndrome have a four-fold increase
in the risk of epilepsy, which results in recurrent seizures that involve loss
of consciousness and convulsions. In infants, seizures can produce m ­ uscles

spasms that are manifested as unusual body movements, or lapses of

­consciousness that affect facial expressions. Seizures in children and adults
with Down syndrome are sometimes triggered by sudden sensory inputs
involving sound, touch, or taste. Severe seizures bring a risk of physical
injury, including head trauma, and can cause incontinence, ­prolonged
­unconsciousness, fatigue, and headaches.
Down syndrome is also associated with a higher risk of obesity, defined
as having a body mass index (BMI) greater than the 95th ­percentile,
adjusted for age and sex. As a consequence of hypothyroidism, d ­ uring
which the hormonally controlled bodily metabolic rate is abnormally
slowed, or because of abnormalities in the balance of energy m ­ etabolism,
children with Down syndrome are twice as likely to develop obesity.
­Obesity is also caused by behavioral tendencies that children with Down
syndrome have, such as inattention, disobedience, and impulsiveness,
which affect their diet and level of physical activity. Childhood obesity
leads to health complications such as type 2 diabetes, hypertension, liver
disease, respiratory problems, and sleep apnea. Obesity in adults with
Down syndrome puts them at a greater risk for osteoarthritis, heart dis-
ease, and stroke.
Acetaminophen, 39 Celiac disease, 7, 38
ADAMTS1 gene, 30 Centromere, 23
Adult stem cells, 47 Cerebellum, 45–46
Alleles, 17 Chorionic villus sampling (CVS),
Allogeneic, 48 11–12
Alternative splicing, 29 Chromosomal rearrangement, 22–24
Aluminium hydroxide, 38 Chronic obstructive pulmonary
Alzheimer’s disease, 9 disease (COPD), 40
Amblyopia, 4–5, 37 Cilia, 33
American Congress of Obstetricians Cochlea, 38
and Gynecologists, 10 Codons, 27
Amniocentesis, 11–12 COL6A1 gene, 30
Amyloid plaques, 29 Combined test, 10
Anemia, 15, 39 Conductive hearing loss, 5, 37
Aneuploidy, 20 Congenital defects
Angiotensin-converting enzyme of gastrointestinal tract, 36
(ACE) inhibitors, 40 hearing loss, 37
Antibiotics, 39 of heart, 2–4, 35–36
Aorta, 4 Congestive heart failure, 3, 40
APP gene, 29 Coronary artery disease, 40
Arteries, 3 Cyanosis, 3
Aspirin, 39 Cytarabine, 40
Atlantoaxial instability, 6
Atria, 3 Delayed language acquisition, 8
Atrial septal defect (ASD), 3, 36 Diabetes, 41
Atrioventricular septal defect (AVSD), Diploid, 18
3, 32–33, 35–36 Diuretics, 40
Autologous, 48 Dosage sensitivity, 28
Autosomes, 12 Down syndrome
causes of, 17–20
Balanced translocation, 23 chromosomal rearrangement,
carrier, 23 22–24
Beta-blockers, 40 extra genes, 26–31
Bismuth subsalicylate, 38 mosaic Down syndrome, 24–26
Blastomere biopsy, 49 trisomy 21, 20–22
Blepharitis, 5, 37 in characteristic physical features,
Body mass index (BMI), 16 1–2
Bronchiolitis, 14, 39 cognitive effects of, 9–10
Brushfield spots, 1 congenital heart defects from, 2–4
contributing factors for, 31–33
Carcinoma, 15 delayed development, 7–8
Cataracts, 4, 36–37 diagnosis of, 10–14

Down syndrome (continued) therapy, 50–51

education for children with, 41–42 Genetic code, 27
experimental drugs for, 45–47 Genetic recombination, 18
gene therapy for, 50–51 Genome-wide association study
health complications of, 14–16 (GWAS), 32
other congenital conditions result Genomes, 18
from, 4–7 Genotypes, 17
preimplantation genetic diagnosis Glaucoma, 5, 37
of, 49–50 Glue ear, 5–6, 37
stem cell therapy for, 47–49
therapies for, 42–43 Haemophilus influenzae, 14, 39
treatment Haploid, 18
congenital defects, 35–38 HDAC inhibitors, 47
health complications, 38–41 Hearing aids, 37–38
Down Syndrome Education Hearing loss. See specific hearing
International, 42 losses
Down Syndrome International, 42 Heterozygous genotype, 17
DSCAM gene, 29–30 Hib vaccine, 39
Ductus arteriosus, 4 Hippocampus, 46
Duodenal atresia, 7, 36 Hirschsprung disease, 6, 36
DYRK1A gene, 29 Histone, 46
Histone deacetylase (HDAC), 47
Echocardiogram, 35 Homozygous dominant alleles, 17
Edwards syndrome, 21–22 Homozygous recessive
Electrocardiogram, 35 genotype, 17
ELND005. See Scyllo-inositol Human genome, 26
Embryonic stem (ES) cells, 47 Hydroxyurea, 39
Epicanthal folds, 1 Hypertension, 40
Epigenetics, 46 Hypothyroidism, 7, 8, 38
Epilepsy, 15–16 Hypotonia, 6
Esophageal atresia, 7, 36
ETS2 gene, 30–31 Ibuprofen, 39
Euploidy, 20 Imperforate anus, 7, 36
Eustachian tube, 6 In vitro fertilization (IVF), 49
Exons, 26 Individualized education program
(IEP), 42
Familial Down syndrome, 23 Individuals with Disabilities
FLJ33360 gene, 33 Education Act (IDEA), 41–42
Fluorescence in situ hybridization Induced pluripotent stem cells (iPS),
(FISH), 22 48–49
Folic acid, 38 Intellectual capacity, 9
Folliculitis, 15, 39 Intellectual disability, 9
FZD6 gene, 33 Intelligence quotient (IQ), 9
Introns, 26
Gametes, 18 Isochromosome, 23
Gastroesophageal reflux disorder ITSN1 gene, 30
(GERD), 7, 38
Genes, 11 Karyotyping, 12, 24–25
modifiers, 32 Klinefelter syndrome, 21

Language acquisition, 43 Pneumonia, 14, 39

delayed, 8 Polycythemia, 15, 39
Lazy eye. See Amblyopia Postlingual hearing loss, 6
Leukapheresis, 39 Preimplantation genetic diagnosis
Leukemia, 15 (PGD), 49–50
Levothyroxine, 38 Prelingual hearing loss, 6
Ligamentous laxity, 6 Prenatal diagnostic testing, 10
Liver disease, 40 Prenatal screening, 10–11
Primary germ layers, 2
Maternal blood screening, 11 Pulmonary artery, 3
Meiosis, 18, 19 Pulmonary hypertension, 3
Meiotic nondisjunction I, 20 Pulmonary vascular disease, 3
Meiotic nondisjunction II, 20
Mesoderm, 2 Quad screen blood test, 10–11
Messenger RNA (mRNA), 27
Mitosis, 20 Recessive allele, 17
Mitotic nondisjunction, 25 Reciprocal translocation, 22–23
Monogenic, 31 Refractive errors, 5
Monosomy, 21 Regenerative medicine, 47
Mosaic Down syndrome, 12, 13, Reproductive system, 8
24–26 Ring chromosome, 23
Mosaicism, 21 RNA splicing, 27
Mutations, 20 Robertsonian translocation, 23
RSV vaccine, 39
National Down Syndrome Society, Scabies, 15
10, 42 Scyllo-inositol, 46
Neuroblastoma, 15 Seizures. See Epilepsy
Neurons, 25 Sensorineural hearing loss, 5, 37
Nonalcoholic fatty liver disease Septa, 2
(NAFLD), 40–41 Short-term memory, 8
Nonreciprocal translocation, 23 SIM2 gene, 29
NPHP4 gene, 33 Single nucleotide
Nuchal fold, 11 polymorphisms, 32
Sinusitis, 14, 39
Obesity, 16, 40 Sleep apnea, 15, 40
Obstructive sleep apnea, 15, 40 Somatic cell nuclear transfer
Occupational therapy, 43 (SCNT), 48
Otitis media, 6, 37, 39 Somatic cells, 25
Sonic hedgehog agonist 1.1
Pantoprazole, 38 (SAG 1.1), 46
Patau syndrome, 21 Speech therapy, 43
Patent ductus arteriosus Stem cells, 26
(PDA), 4, 36 therapy, 47–49
Penicillium, 18 Streptococcus pneumoniae, 14, 39
Phenotypes, 17
Phlebotomy, 39 Tetrad, 31
Physical therapy, 42 Tetralogy of Fallot (TOF),
Pluripotent, 47 4, 36
Pneumococcal vaccine, 39 Thrombocytopenia, 15, 39

TKNEO gene, 51 United States Education for All

Tonsillitis, 14, 39 Handicapped Children Act of
Totipotent, 47 1975, 41
Tracheoesophageal fistula, 7, 36 Urinary tract infections, 39
Transcription factor, 27, 30
Transient myeloproliferative disorder Veins, 3
(TMD), 15, 39–40 Ventricles, 3
Translation, 27 Ventricular septal defect (VSD),
Translocation Down syndrome, 12, 3, 36
13, 23–24 Viral pathogen respiratory syncytial
Triple X syndrome, 21 virus (RSV), 14, 39
Trisomy 21, 12, 13, 20–22 Vitamin D, 38
Trophectoderm biopsy, 49
Tumor angiogenesis, 30 XIST gene, 51
Tumor suppressor, 30–31
Turner syndrome, 21 ZSCAN4 gene, 51
A. Malcolm Campbell, Editor
• Hereditary Blindness and Deafness: The Race for Sight and Sound by Todd T. Eckdahl
• Genetic Diseases or Conditions: Cystic Fibrosis, The Salty Kiss by Todd T. Eckdahl
• Gradual Loss of Mental Capacity from Alzheimer’s by Mary E. Miller
• Hemophilia: The Royal Disease by Todd T. Eckdahl
• Sickle Cell Disease: The Evil Spirit of Misshapen Hemoglobin by Todd T. Eckdahl
• Auto-Immunity Attacks the Body by Mary E. Miller
• Huntington’s Disease: The Singer Must Dance by Todd T. Eckahl
• Nerve Disease ALS and Gradual Loss of Muscle Function: Amytrophic Lateral Sclerosis
by Mary E. Miller
• Infectious Human Diseases by Mary E. Miller
• Breast Cancer: Medical Treatment, Side Effects, and Complementary Therapies
by K.V. Ramani, Hemalatha Ramani, B.S. Ajaikumar, and Riri G. Trivedi
• Acquired Immunodeficiency Syndrome (AIDS) Caused by HIV by Mary E. Miller

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